Diarthrodial or synovial joints allow movement and transfer of load between bones. These two critical functions play a major role in athletic performance and disease or injury of these joints, in turn, has a major impact on athletic performance in man and in animals. For example, one of the most important causes of lameness among equine athletes is primary joint disease of the diathrodial or synovial joints. In the past 25 years much knowledge has been gained regarding the treatment and/or prevention of disease processes affecting synovial joints and, in particular, in the understanding of disease and trauma of articular cartilage (see, McIlwraith & Trotter, “JOINT DISEASE IN THE HORSE”, W. B. Saunders, 1996 (ISBN 0-7216-5135-6)).
As a brief overview, the highly mobile diarthrodial joints of the body have similar structures and components including: the joint capsule, or outer membrane, which encases the joint; collateral ligaments which are intra-capsular and provide support and stability for the joint (these work in conjunction with supporting muscle, other extra-capsular ligaments, tendons and connective tissue); articular cartilage which covers the ends of the articulating bones within the joint; subchondral bone which provides structural support to the overlying articular cartilage; the synovium, a modified mesenchyme; and synovial fluid which lubricates and nourishes the joint surfaces.
The joint capsule consists of a thick fibrous portion, which is lined by a thinner subsynovium (lamina propria) and the synovium (synovial membrane). The synovium or inner lining of the joint capsule consists of cells, synoviocytes, which have both secretory and phagocytic functions. Synovial lining cells synthesize hyaluronan (hyaluronic acid or HA) that is secreted into the synovial fluid, which occupies the intra-articular space.
Synovial fluid is essentially an ultrafiltrate of plasma with the exception of the hyaluronan (a non-sulfated glycosaminoglycan lacking a protein core) secreted by the synovium. Synovial fluid is normally highly viscous due to its hyaluronan content and plays a crucial role in maintaining healthy cartilage and protecting the joint surface.
Hyalauronan is also known as hyaluronic acid (HA). This important glycosaminoglycan (GAG) is an integral part of both synovial fluid and articular cartilage. Within the articular cartilage, hylauronan provides viscoelastic properties allowing ease of motion between opposing surfaces and increasing compressive resistance. Within the synovium, hyaluronic acid, as a component of synovial fluid, provides an effective barrier regulating the introduction of plasma components. Under normal conditions, the body will synthesize sufficient amounts of base components to maintain and grow healthy articular cartilage, while limiting the production and release of destructive proteinases, inflammatory mediators and catabolic enzymes.
Articular cartilage is a matrix of proteoglycans, chondrocytes, and collagen, which has a translucent or glasslike (hyaline) appearance due primarily to its high water content. Articular cartilage absorbs shock from mechanical forces and provides a smooth surface so that bone ends may glide easily across one another. Articular cartilage is comprised of about 70% water (up to about 80% water in neonatal animals), collagen, proteoglycans, and chondrocytes. Most of the collagen found in articular cartilage is type II collagen which provides tensile strength to the cartilage. This versatile protein provides elasticity and the structural framework of the cartilage matrix.
Proteoglycans, the other major solid component of the articular cartilage matrix consist of one or more glycosaminoglycan chains covalently bonded to a protein core. Due to their dense negative ion content, these molecules are able to attract and retain water within the cartilage formation specifically for lubrication. Proteoglycans provide the unique mechanical properties for resiliency and recovery under compressive forces.
The major proteoglycans found in cartilage are chondroitin sulfate, dermatan sulfate, keratan sulfate and hyaluronan. (Heparin sulfate is also a proteoglycan, although it is not a component of articular cartilage.) Newer names for proteoglycans sometime reference function of the core protein within the molecule, e.g., aggregan (found in chondroitin sulfate and keratin sulfate), a large proteoglycan aggregates with hyaluronin, or location, e.g., decorin (dermatan sulfate), which decorates type I collagen fibrils, or to primary structure, biglycan which has two glysoaminoglycan chains.
Chondrocytes are active cells within the cartilage matrix, which manufacture new collagen and proteoglycan molecules while excreting enzymes, which aid in removal of damaged cartilage and proteoglycans.
Under normal conditions, the body maintains the synovial joint in state of homeostasis through a variety of complex hormonal and mechanical feedback mechanisms. Two types of insult or injury can upset the delicate homeostatic balance. Repeated trauma or stress (slow chronic insult) to the joint during everyday use, e.g., athletic training or performance, is often the inciting cause of joint inflammation and loss of homeostasis. Initially, such stress results in only soft tissue inflammation in the form of synovitis or capsulitis (e.g., traumatic synovitis). Cartilage damage may or may not initially be present in the early stages of stress related injury or inflammation. However, the release of inflammatory mediators into the joint such as prostaglandins, cytokines, lysosomal enzymes and free radicals can lead to damage of articular cartilage and can cause cartilage degradation and can lead to development of degenerative joint disease (DJD).
A second type of insult or injury, the osteochondral defect, e.g., a chip fracture, is often associated with an acute mechanical failure or traumatic injury, e.g., an acute racing or training injury, although, such a fracture can be due to secondary complications associated with chronic DJD. Under this scenario, the lesion often starts as a traumatically induced defect in the articular cartilage. This may occur as a fragmentation of the original tissue from the joint margins or other defect which compromises the surface and integrity of the articular cartilage. Exposure of the supporting subchondral bone to synovial fluid and the intermittent pressures of the synovial fluid generated by repeated joint movement (repeated stress and trauma of training or racing) can lead to progressive subchondral bone sclerosis and eventual dislodging of the chip or bone fragment. Left untreated, the resulting damage often becomes progressive and DJD results (see, e.g., Nixon et al., “EQUINE FRACTURE REPAIR”, W. B. Saunders Co., 1996 (ISBN 0-7216-6754-6)).
Under either scenario, once compromised, the damage to articular cartilage is usually permanent. In general, once damaged, therapy is normally directed at limiting or reducing joint inflammation, limiting the release of inflammatory mediators, removal of the inciting cause (e.g., the chip) and replacement of synovial fluid components. These measures are combined with a period of rest to allow for healing and fibrocartilage deposition at the affected area. The long term therapeutic objective is directed at slowing the progression of degenerative processes and controlling the clinical signs of DJD. Prevention is often aimed at limiting joint inflammation before damage to cartilage occurs and in providing proper nutritional support.
There have been countless therapeutic approaches for management of joint disease. Chief among these is the nutritional supplementation of metabolic precursors to the diet to aid in the biosynthesis of proteoglycans, GAG's, hyaluronan, and collagen. Nutritional supplements or “nutraceuticals” such as COSEQUIN® (see, U.S. Pat. Nos. 5,364,845 and 5,587,363) and GLC 5500® (see, PCT International Publication No. WO 0132188 A1) are recommended for oral supplementation of the diet for providing the necessary metabolic precursors for aiding the body in reparation of joint injury.
In particular, a list of metabolic precursors which have been used as oral supplementation for the production of articular cartilage are found e.g., in PCT International Publication No. WO 0132188 A1 to Madere. These oral supplements include, chondroitin sulfate, a glycosaminoglycan polysaccharide, which is a primary component of articular cartilage comprising an amino sugar and an organic acid or sugar. Chondroitin sulfate is broken down into sulfate disaccharides and N-Acetyl galactosamine. D-Glucuronic acid is a key substrate comprising one half of the hyaluronan molecule, the other being N-Acetyl D-glucosamine. Chondroitin sulfate, as CS4 and CS6 within the body, are thought to be an essential glycosaminoglycans which bind water to the articular cartilage matrix and are necessary for the formation of proteoglycans.
Another oral supplement, glucosamine, as glucosamine 5-phosphate, is naturally occurring within the body and is a component in the biosynthesis of glycosaminoglycans, proteoglycans, hyaluronan, and collagen. Glucosamine is available in exogenous forms, glucosamine sulfate sodium, glucosamine hydrochloride and N-Acetyl D-Glucosamine. These forms are reported to be orally bioavailable in mammals.
Methylsulfonymethane (MSM), also used in oral supplements, is an integral part of hemoglobin and body tissue, and is essential for the synthesis of connecting tissues, collagen and the essential amino acids methionine and cysteine. Sodium ascorbate is an oral supplement that needed for collagen production and aids in the body's ability to utilize manganese. In theory, oral supplementation and subsequent biosynthesis of the metabolic precursors aid in the production of new articular cartilage while aiding in regulating the damaging effects of destructive enzymes. Exogenous glucosamine is believed to allow the body to exceed the natural rate-limiting thresholds whereby glucosamine becomes the stimulant in the production of proteoglycans and GAGs. Exogenous oral glucosamine is also believed to stimulate chondrocytes to produce more collagen and enhance articular cartilage metabolism.
Numerous other disclosures also suggest the introduction of nutritional supplements as therapy for the treatment of connective tissues. U.S. Pat. No. 3,683,076 to Rovati et al. teaches that glucosamine sulfates are useful to treat arthritic conditions. U.S. Pat. No. 3,697,652 to Rovati et al. discloses that N-acetyl glucosamine can be used to treat degenerative afflictions of the joints. U.S. Pat. Nos. 5,364,845, 5,587,363 and 6,492,349 (to Henderson) show that glucosamine, chondroitin and manganese are used to protect and repair connective tissue. In U.S. Pat. No. 5,840,715 to Florio, N-acetyl glucosamine sulfate, chondroitin sulfate, gamma linolenic acid ercosapentaenoic acid and docosahexaneoic acid, and manganese aspartate are combined to treat arthritis symptoms. U.S. Pat. No. 5,916,565 to Rose et al. teaches a composition comprised of D-glucosamine hydrochloride, chondroitin sulfate, cayenne, ginger, turmeric, yucca, Devil's Claw, nettle leaf, Black Cohosh, alfalfa, and celery seeds to repair and maintain damaged tissues in joints of vertebrates. In U.S. Pat. No. 5,922,692, Marino discloses that glucosamine sulfate and chondroitin sulfate can be added to foodstuffs.
However, despite the relative commercial success of many of the “nutraceutical” preparations, controversy abounds as to their relative levels of effectiveness in actually preventing or treating damage to articular cartilage and/or DJD. For example, one study conducted by Luitpold Pharmaceutical, Inc. found that no anti-inflammatory or chondroprotective effect could be demonstrated when oral glucosaminoglycans (GAG's) were used to treat equine DJD.
Numerous parenteral intra-articular and systemic (intramuscular and intravenous) approaches to therapy have also been tried. For example, hyaluronate sodium (hyalurionic acid or “acid”) has been used extensively as an intra-articular and intravenous treatment for human and animal joint disease. LEGEND®, for example, available from Bayer Corporation in Shawnee Mission, Kans., is approved for both intravenous and intra-articular use in the horse. U.S. Pat. No. 4,782,046 to Brown et al. describes an ultrapure form of hyaluronic acid prepared from group C streptococcal organisms. U.S. Pat. No. 4,808,576 to Schultz et al. disclose methods of administration of hyaluronic acid other than intra-articularly, e.g., intramuscularly or topically. Recently, there has even been a product introduced, CONQUER™ (Kinetic Technologies, Inc., Lexington, Ky.) for oral administration of hyaluronic acid.
Other products for parenteral administration include e.g., chondroitin sulfate for intramuscular use available from Syntex S. A. Argentina; polysulfated glycosaminoglycan (PSGAG) for intra-articular and intramuscular injection which is available as ADEQUAN.®. from Luitpold Pharmaceuticals, Inc., Shirley N.Y. and N-acetyl glucosamine for intramuscular or intra-articular injection (see U.S. Pat. No. 3,697,652 to Rovati et al.). Each of the afore-mentioned preparations has met with varying degrees of success and many, particularly HA and PSGAG still enjoy widespread use in the treatment and prevention of DJD in man and in animals. The risks and rewards and overall benefit of certain of these treatment modalities is controversial, however, as evidenced e.g., by “Hyaluronic Acid Rules in Severe Joint Problems”, HORSE JOURNAL, Vo. 9, No. 5 pp. 3–6, May 2002.
More importantly, prior to the present invention there has not been a single effective composition specifically formulated for intra-articular use which combines an optimal combination of active agents which can be used for intra-articular treatment of OA and/or DJD. In particular, there exists a need in the art for a composition formulated for intra-articular use which uniquely combines synergistically active agents for use as a adjunct to surgical intervention, e.g., as a joint lavage and/or post surgical treatment. There is especially a need in the art for a composition which can be used during and post surgically to aid in the physical removal (lavage) of detrimental and degenerative post surgical joint debris, while simultaneously acting to lubricate joint surfaces, protect the remaining articular cartilage from further enzymatic degradation and provide in situ “fuel” for synoviocyte and chondrocyte production of endogenous hyaluronan and proteoglycans.
Likewise, prior to the present invention there has not been a single effective composition specifically formulated for intra-articular use and/or parenteral (e.g., intravenous or intramuscular) use which combines an optimal combination of active agents which can be used for intra-articular and/or parenteral treatment of traumatic synovitis. In particular, there exists a need in the art for a composition formulated for intra-articular use or systemic use which combines synergistically active agents to treat and/or prevent traumatic synovitis.